We will investigate the pharmacology of gonadotropin releasing factor (GnRH) antagonists by designing constrained analogs. In human, we and others have recently demonstrated the conceptual advantages of the use of GnRH antagonists (Nal-Glu) over that of GnRH agonists for contraceptive purposes in male, for in vitro fertilization and for the management and/or treatment of a number of sex steroid dependent pathologies including endometriosis. It is not yet fully demonstrated that agonists and antagonists interact at the same or different locus(i) on the receptor to achieve their effects. Practically, agonists and antagonists have to be administered by injection and agonist preparations with long duration of action are commercially available. The fact that agonists first stimulate gonadotropin release (which antagonists do not) and do not inhibit gonadotropin secretion to the same extent as do antagonists is considered a significant disadvantage. Using the classic, "informed trial-and-error method of traditional medicinal chemistry" for the development of linear GnRH antagonists, we have identified a large family of highly potent and very long acting antagonists with insignificant histamine releasing activity. The fact that neither agonist nor antagonists are orally active is another disadvantage. In a number of reported cases, non-peptide antagonists of peptide hormones have been developed that are orally active. Evidence that these peptidomimetics do not interact with their respective receptors at loci identical to that at which peptide antagonists act suggests that they may not have the same and often desired (as in the case of GnRH) pharmacological properties of their peptidic counterparts. Because we have now a well defined model of the solution conformations of a representative number of GnRH antagonists through the extensive study of highly constrained (mono and bicyclic) analogs by NMR and computer simulations, we propose to modify these constrained molecules by the introduction of turn mimetics with the hope of altering (improving) their oral bioavailability without altering their locus of action on the receptor and thus retain their desired pharmacological properties. Because of our interest in the evolution of this hormone/neuropeptide and in these novel GnRH analogs, as a logical starting point in the development of structure activity relationships, we plan to isolate (in collaboration with Dr. Nancy Sherwood) characterize, purify and synthesize novel native GnRH molecules. We will also design and synthesize a limited number of superagonists and antagonists of these molecules for collaborative field studies on fish spawning and growth and use the feedback from these bioassays in different species to garner an understanding of parallel ligand/receptor evolution.